Positron Emission Tomography (PET) is a molecular imaging technology that is increasingly used for detection of various diseases, such as Alzheimer's disease, cardiovascular and metabolic diseases, cancer, AIDS, Parkinson's disease and other disorders. Disease is a biological process, and molecular imaging provides a sensitive and informative means to identify, study, and diagnose the biological nature of disease early in and throughout its evolution, as well as to provide biological information for development and assessment of therapies. For example, PET whole body imaging in cancer provides the means to (i) identify early disease, (ii) differentiate benign from malignant lesions, (iii) examine all organs for metastases and (iv) determine therapeutic effectiveness.
PET imaging systems create images based on the distribution of positron-emitting isotopes in the tissue of a patient. The isotopes are typically administered to a patient by injection of probe molecules that comprise a positron-emitting isotope (e.g., carbon-11, nitrogen-13, oxygen-15, or fluorine-18) covalently attached to a molecule that is readily metabolized or localized in the body or that chemically binds to receptor sites within the body. Positron emitters of Cu, Zn, K, Br, Rb, I, P, Fe, Ga and others can also be used.
PET probes and drugs are being developed together—in low mass amounts, as molecular imaging probes to image the function of targets without disturbing them, and in mass amounts to modify the target's function as a drug. Common tissue concentrations of PET probes are in the range of pico- to femtomoles per gram. Over 500 molecular imaging probes have been developed and consist of various labeled enzyme and transporter substrates, ligands for receptor systems, hormones, antibodies, peptides, drugs (medical and illicit), and oligonucleotides. For PET probes the short half-lives of the positron emitters require that synthesis, analysis and purification of the probes are completed rapidly.
Common pharmaceuticals radiolabeled with F-18 include, but are not limited to 2-deoxy-2-[F-18]-fluoro-D-glucose (18F—FDG), 3′-deoxy-3′[F-18]-fluorothymidine (18F—FLT), 9-[4-[F-18]fluoro-3-(hydroxymethyl)butyl]guanine (18F—FHBG), 9-[(3-[F-18]fluoro-1-hydroxy-2-propoxy)methyl]guanine (18F—FHPG), 3-(2′-[F-18]fluoroethyl)spiperone (18F—FESP), 4-[F-18]fluoro-N-[2-[1-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (18F-p-MPPF), 2-(1-{6-[(2-[F-18]fluoroethyl)-10 (methyl)amino]-2-naphthyl}ethylidine)malononitrile (18F—FDDNP), 2-[F-18]fluoro-amethyltyrosine, [F-18]fluoromisonidazole (18F—FMISO), 5-[F-18]fluoro-2′-deoxyuridine (18F—FdUrd), and 2′-deoxy-2′-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F—FMAU). Other common radiolabeled compounds include 11C-methionine and 11C-acetic acid.
The synthesis of the [F-18]-labeled molecular probe, 2-deoxy-2-[F-18]-fluoro-D-glucose (18F—FDG), is based on three major sequential synthetic processes: (i) Concentration of the dilute [F-18]fluoride solution (1-10 ppm) that is obtained from the bombardment of target water, [O-18]H2O, in a cyclotron; (ii) [F-18]fluoride substitution of the mannose triflate precursor; and (iii) acidic hydrolysis of the fluorinated intermediate. Presently, [F-18]FDG is produced on a routine basis in a processing time (or cycle time) of 25 about 50 minutes using macroscopic commercial synthesizers. These synthesizers consist, in part, mechanical valves, glass-based reaction chambers and ion-exchange columns.
Other target probes such as, for example, 18F—FLT or 18F—FMAU, are more complex and require additional steps such as HPLC and intermediate purifications.
Instrument for carrying out synthesis of more complex radiolabeled targets require more complex and flexible equipment.
Most of known radiosynthesis modules have electronic equipment, reagent and radiation-handling components all in one mini-cell. This presents risk of radiation exposure to the operator handling the instrument and to the sensitive equipment inside such modules, which have to be serviced or replaced frequently. Furthermore, in most of the radiosynthesis systems reagents have to be replenished after each run, which subjects the user to radiation exposure and allows limited flexibility in production of wide range of PET probes in an efficient manner.
As such, there is a need for safer and more efficient systems that are capable of providing the flexibility to produce a wide range of probes, biomarkers and labeled drugs or drug analogs efficiently and in a safe to the user manner and at the same time capable of expediting chemical processing to reduce the overall processing or cycle times and production costs.